<sup>18</sup>FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed

doi:10.4236/jct.2012.324049

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Journal of Cancer Therapy, 2012, 3, 372-378

http://dx.doi.org/10.4236/jct.2012.324049 Published Online September 2012 (http://www.SciRP.org/journal/jct)

18FDG-PET/CT Is a Useful Tool in Staging Procedure

before Chemo-Radiotherapy in Patients with Limited

Disease Small-Cell Lung Cancer. Pattern of Failure and

Survival Is Analyzed

Anne Winther Larsen, Azza A. Khalil, Peter Meldgaard, Marianne M. Knap

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Email: [email protected]

Received July 29th, 2012; revised August 30th, 2012; accepted September 12th, 2012

ABSTRACT

Background: Th e purpose of this study was to evaluate the use of 18FDG-PET/CT in staging procedure, the pattern of

failure and survival in patients with small-cell lung cancer limited disease (LD-SCLC) undergoing chemo-radiotherapy.

Methods: A total of 79 LD-SCLC patients were treated with a combination of chemotherapy and chest radiotherapy.

Radiotherapy of the tumour and the pathological lymph nodes was performed either as 45 Gy twice-daily or 46 - 50 Gy

once-daily. 18Fluro-2-deoxy-D-glucose (18FDG)-PET/CT was performed in 35 patients as part of the staging procedure.

Results: With a median follow-up time of 17 months 6% developed isolated loco-regional failures while 57% deve-

loped distant metastases. No isolated regional failures were seen. Median overall survival was 22 months. Patients

staged with a 18FDG-PET/CT had a significantly lower incidence of distant failures and a significantly improved overall

survival compared with patients only staged with a CT scan (p = 0.03) (median ov erall surv ival of 34 versu s 17 months,

respectively). Conclusion: The pattern of failure showed a high risk of distant metastases but a low incidence of iso-

lated loco-regional failures. Patients staged with an 18FDG-PET/CT had a significantly lower incidence of distant fail-

ures and better overall survival, indicating that 18FDG-PET could be beneficial in patients with LD-SCLC before decid-

ing on treatment regimen.

Keywords: Small-Cell Lung Cancer; Limited Disease; Thoracic Radiotherapy; Positron Emission Tomography;

Pattern of Failure

1. Introduction

Small-cell lung cancer (SCLC) accounts for about 12% -

15% of all lung cancers. It is an aggressive disease with a

rapid doubling time and a considerable potential for early

development of metastases. Only 20% - 30% of SCLC

patients have limited disease (LD) at diagnosis and hence

considered potentially curable. SCLC has a high sensiti-

vity to chemotherapy (CT) and radiotherapy (RT), and an

improvement in overall survival was achieved when CT

and RT were combined [1,2]. Optimal dose, timing and

fractionation of RT have been investigated previously but

results are conflicting [3-5]. Despite the high sensitivity

to treatment, most patients experience a relapse of dis-

ease, particularly with distant metastases, but also in the

form of local and regional failures, and overall survival

rate is always low. Optimal treatment strategies should

partly be based on an understanding of patterns of failure

in standard therapies. Moreover, accurate staging is of

utmost importance in the management of SCLC. During

the last decade, 18FDG-PET scans have been incorpo-

rated in the staging procedure in some institutes, but the

documentation for its usefulness is not as robust as in

non-small-cell lung carcinoma (NSCLC) [6].

The aim of this study was to present the treatment re-

sults of consecutively enrolled LD-SCLC patients un-

dergoing radical CT and RT over a four-year period par-

ticularly focusing on pattern of failu re and effect of PET/

CT.

2. Materials and Methods

2.1. Patient Population

All consecutive LD-SCLC patients treated with chest RT

at the Department of Oncology at Aarhus University

Hospital, Denmark between 2007 and 2010 were in-

cluded. The inclusion criteria were: a pathologically pro-

ven diagnosis of SCLC, a staging confirming LD and

18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with

Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed 373

initiation of treatment with RT in curative doses regard-

less of whether the patient actually completed the treat-

ment.

The diagnostic work-up was performed at three dif-

ferent institutes in Denmark and includ ed complete blood

count, bronchoscopy with biopsy and CT imaging of the

chest and abdomen. CT/MR scans of the br ain and bones

were only performed if clinically indicated in accordance

with clinical guidelines at our department at the time of

study. 18FDG-PET/CT scans were gradually incorpo-

rated as part of the diagnostic process during the study

period.

Data on patient characteristics, treatment and relapses

were obtained from patient records. The date of diagnosis

was defined as the date of the first positive biopsy. The

clinical staging by the TNM system was retrospectively

determined by reviewing the CT- and PET-scans and

done by the authors. The date of death was documented

in our electronic patient file system. If follow-up was in

another department the patient record and scans were

retrieved. Two patients had another malignant disease at

the time of diagnosis and were thus excluded from the

analysis.

2.2. Chemotherapy

The patients were treated with a standard combinatio n of

a platinum derivative and etoposide given every third or

fourth week. Dosage of carboplatin was AUC5 and cis-

platin dose was 75 mg/m2; both given on day one of

every cycle. Etoposide dose was 120 mg/m2 i.v. or 240

mg/ m 2 orally on day 1, 2 and 3 of every cycle.

2.3. Radiation Therapy

The RT was given twice-daily with 45 Gy in 30 F, 10 F

per week and either concomitan t with or sequen tial to CT

(Table 1). A few patients with large tumours, comorbi-

dity and advanced age were treated once-daily regime

(46 - 50 Gy in 23 - 25 F, 5 F per week) to lo wer the risk

of acute toxicity.

The treated volume was planned from a pre-treatment

CT scan and a PET/CT scan if available. Elective irradia-

tion of uninvolved lymph nodes (ENI) was not per-

formed. The gross target volume (GTV) for the primary

tumour (GTVt) and pathological lymph nodes (GTVn)

was delineated on the planning 3D-CT scans by two

clinical oncologists assisted by a radiologist using both

lung window and mediastinal window and guided by the

visual interpretation of the PET/CT scan. Nodal involve-

ment was defined as nodes > 1 cm in the short axis. A

margin of 0.5 cm was added to the GTVt and GTVn to

create respective Clinical Target Volumes (CTV) modi-

fied for overlap with bones and major blood vessels in

Table 1. Treatment and patient characteristics.

Patient characteristics No. patients

Median age in year s (range) 64 (44 - 78)

Gender: male/female 34/45

PS: 0/1/2 37/40/2

Stage (TMN): IB/IIA/IIB/IIIA/IIIB 2/2/2 27/46

RT total dose in Gy: 45/46/50 66/3/10

Timing of RT: concurrent/sequential 70/9

Series of chemotherapy: 2/3/4/5/6/7 2/2/37/3/34/1

PCI: yes/no 69/10

PS: ECOG Performance Status; RT: radiotherapy; PCI: prophylactic cere-

bral irradiation.

the mediastinum. The CTV volumes were expanded to

the Internal Target Volume (ITV) by adding another 0.5

cm in all directions. The Plann ing Target Volume (PTV)

was then achieved by adding 0.5 mm laterally and 0.8

mm cranio-caudally to th e ITV.

The spinal cord, lungs, heart and oesophagus were

contoured as organs of risk. The tissue constraints were a

maximum dose of 45 Gy to the spinal-cord at any point

and a maxi mum of 50 Gy t o maxi mum 2 0% of t he hear t.

The percentage of the total lung vo lume receiving 20 Gy

(V20) was maximum 40%. Mean lung dose (MLD) was

maximum 19 Gy.

Patients with a good performance (PS = 0 - 1) at the

end of the CT-RT and with no signs of disease progres-

sion were offered prophylactic cranial irradiation (PCI).

The PCI dose given was 2 5 Gy in 1 0 F, 5 F pe r week .

2.4. Follow-Up

After completion of treatment, patients were followed

with CT imaging of chest and abdomen and clinical

evaluation every third to fourth months in the first year

and every sixth months in the following years. Imaging

of brain and bones was only performed if clinically

indicated. If there was sign of relapse, the CT scan was

evaluated by a multidiscip linary tumour board to confirm

the evidence of radiological tumour progression. If re-

lapse was considered likely, a biopsy was performed. If a

biopsy was not possible, a PET scan would be used to

confirm the diagnosis of relapse, except in patients with

metastases in the brain. A few patients, however, pro-

gressed clinically in such a way that a biopsy became

unnecessary. Date of relapse was defined as the date of a

positive CT scan, even if a biopsy or a PET-scan was

subsequently carried out to confirm the recurrence. All

patients received all follow-up scans and no were lost to

follow-up.

Local relapse was defined as recurrence in the ra-

diation field, and regional relapse as recurrence in the

18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with

Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed

374

regional lymph nodes of the mediastinum or supracla-

vicular region outside of the original PTV. Distant me-

tastases were defined as metastases anywhere else than

mentioned above. All RT treatment plans were evaluated

by the authors to define the loco-regional relapses.

2.5. Statistical Analysis

The statistical analyses were performed using SPSS 18.0

for windows. The survival functions were calculated

from the time of diagnosis for the endpoints and overall

survival by the methods of Kaplan and Meier. The in-

cidence of local, regional and distant relapse was cal-

culated from the time of diagnosis. Patients were cen-

sored from the date of last follow-up. The log rank test

was used for comparison of groups.

3. Results

3.1. Patient Characteristics

The median follow-up time was 17 months (range, 3 - 48

months) for all patients and 28.5 months (range, 14 - 48

months) for patients still alive at the time of analysis.

Treatment and patient characteristics are summarized in

Table 1. Ten patients (13%) were diagnosed in 2007, 23

patients (29%) in 2008, 30 patients (38%) in 2009 and 16

patients (20%) in 2010. During the diagnostic process, all

patients had a CT scan of the chest and abdomen, but

only 8 patients (10%) had a CT/MR scan of the brain.

Thirty-five patients (44%) underwent a FDG-PET scan

as part of the diagnostic process, and this was mainly

patients diagnosed in 2009 and 2010. The frequency of

PET scans in patients diagnosed in 2007 was 20%, 17%

in 2008, 50% in 2009 and 88% in 2010 .

The median follow-up time for patients still alive at

the time of analysis was in the PET-staged group 25

months (range, 14 - 48 months) and 33.5 months (range,

17 - 48 months) in the CT-staged group. Sixty-two pa-

tients (78%) received carboplatin and 17 patients (22%)

cisplatin. All patients received the planned dose of RT.

For patients receiving RT concomitant with CT the me-

dian time from CT to start of RT was 29 days. The size

of the chest radiation fields varied considerably. One

patient had a pathological lymph node in the supraclavi-

cular region as the only disease manifestation and RT

was only performed in the affected supraclavicular re-

gion resulting in a very small radiation field.

The GTV of the primary lung tumour and the patho-

logical lymph nodes had a median value of 93 cm3 (range,

3 - 494 cm3); PTV 581 cm3 (range, 86 - 2055 cm3). The

median V20 was 29% (range, 10% - 52%) and the MLD

was 14 Gy (range, 6 - 24 Gy). Four patients had a V20

exciding the tissue constraints of maximum 40% (41%,

42%, 44% and 52%, respectively) because of special cir-

cumstances specified in the patients records.

Prophylactic cerebral irradiation (PCI) was given me-

dian 19 days (range, 0 - 138 days) after the patient had

finished chemotherapy. The most common reason not to

receive (PCI) was deterioration of the patient’s general

condition.

3.2. Pattern of Tumour Recurrence

At the end of analysis 50 of the 79 patients (63%) had a

recurrence of disease.

Figure 1 illustrates pattern of first failure. Seventeen

patients (22%) had a local relapse and five patients (6%)

a regional relapse. No patients had isolated regional

failure. Forty-five patients (57%) developed distant meta-

stases and 15 of these patients (33%) had synchronously

loco-regional relapse.

The most common sites to develop the first distant

metastases were the liver (n = 18), bones (n = 11) oppo-

site lung (n = 10) and the brain (n = 8). Figure 2 shows

the incidence of distant relapse is significantly different

between the PET/CT-staged patients and the CT-staged

patients (p = 0.03). Fifteen of the 35 PET/CT-staged

patients (43%) developed distant failure compared with

30 of the 44 CT-staged patients (68%). No significant

difference was seen in loco-regional relapses; 23% ver-

sus 27%, respectively (p = 0.2) .

The incidence of local relapse was 15% (95% Con-

fidence Interval (CI): 10% - 20%) after 12 months and

30% (95% CI: 23% - 37%) after 24 months, for regional

relapse 6% (95% CI: 3% - 9%) after 12 months and 8%

(95% CI: 4% - 12%) after 24 months, while the incidence

for distant metastases was 43% (95% CI: 37% - 49%)

after 12 months and 58% (95% CI: 52% - 74%) after 24

months (Figure 3).

3.3. Survival

The median overall survival for all patients was 22

months (95% C I: 16 - 28 m ont hs) with a one-year overall

4 1

First failure

Local (n=17)

Regional (n=5)

Distant (n=45)

Figure 1. Pattern of first failure showed as local, regional

and/or distant relapse.

18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with

Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed 375

Months from dia

nosis to rela

50403020100

Incidence of distant metastases

1,0

0,8

0,6

0,4

0,2

0,0

PET-CT

(n=35)

(n=44)

p=0.03

1.0

0.8

0.6

0.4

0.2

0.0

Figure 2. The incidence of distant metastases in all 79 pa-

tients related to the pre-treatment staging procedure with

PET/CT or CT.

Months from diagnosis to relapse

50403020100

Incidence of relapse

1,0

0,8

0,6

0,4

0,2

0,0

Distant metastases

Local relapse

Regional relapse

1.0

0.8

0.6

0.4

0.2

0.0

Figure 3. The incidence of local relapses, regional relapses

and distant metastases. Each site is analyzed for all 79 pa-

tients.

survival of 72% (Standard deviation (SD): 67% - 77 %), a

two-year survival of 45% (SD: 39% - 51%) and a

three-year survival of 28% (SD: 22% - 34%) (Figure 4).

Figure 5 shows a significantly better overall survival

Months from diagnosis

50403020100

Overall survival

1,0

0,8

0,6

0,4

0,2

0,0

n=79

1.0

0.8

0.6

0.4

0.2

0.0

Figure 4. Overall survival of all 79 patients with LD-SCLC

treated with chemo-radiotherapy.

Months from diagnosis

50403020100

Overall survival

1,0

0,8

0,6

0,4

0,2

0,0

PET-C T

(n=35)

(n=44)

p=0.03

1.0

0.6

0.4

0.2

0.0

Figure 5. Overall survival of all 79 patients related to the

pre-treatment staging procedure with PET/CT or CT.

in the PET/CT-staged patients with a median overall sur-

vival of 34 versus 17 months in the CT-staged patients (p

= 0.03).

When stratifying the median survival for Eastern Co-

18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with

Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed

376

operative Oncology Group status (0 versus 1), stage, gen-

der, RT schedule (twice-daily RT versus once-daily),

concomitant CT-RT versus sequential, cisplatin versus

carboplatin and the number of cycles of CT; none showed

any significant difference in overall survival.

3.4. Treatment Time

The median overall treatment time (from start of any

treatment to the end of radiotherapy) was 57 days (range;

25 - 246 days). We stratified the patients in three groups

of equal size according to their overall treatment time

and compared the surv ival between the gro ups, but found

no significant difference in the overall survival (p = 0.9).

3.5. Deaths

At the time of analysis, 49 patients (62%) had died.

Seven patients died without a diagnosed relapse; one pa-

tient died of febrile neutropenia during chemotherapy

and the death was related to the treatment. One patient

died 2.5 months after end of treatment with symptoms of

radiation pneumonitis. The V20 for this patient was 34%

and the MLD 18 Gy. The last five patients died of causes

not related to the treatment or to lung cancer.

4. Discussion

These data describe the outcome of a consecutive patient

population over a period of four years. The survival data

are comparable with other retrospective consecutive stu-

dies of non-selected patients [7,8].

We stratified for differences in patient characteristics

and treatment and found no significant difference in

overall survival, which was expected due to the low

number of patients. However, did we observe a sig-

nificantly improved overall survival for the 44% of the

patients staged with 18FDG-PET/CT scans. Additionally,

these patients had a lower incidence of distant failure;

43% versus 68%. This difference most likely indicates a

more exact staging in the PET/CT group with some

patients with extended disease (ED) erroneously staged

with limited disease in the CT-staged group. However, as

patients staged with a PET/CT scan were primarily

diagnosed in 2009 and 2010, the median follow-up time

for these patients was shorter than for the CT-staged

group (25 months versus 33.5 months, respectively for

surviving patients) and this could influence the result.

A PET scan was found to be superior to a CT scan in

the detection of lymph nodes and distant metastases in

NSCLC and is now established in th e staging of NSCLC

patients [9]. However, the documentation for the use of

PET in SCLC is not as robust as in NSCLC [6], and its

usefulness is still debated. Studies have been made to

evaluate the stage migration phenomenon in SCLC pa-

tients staged using a PET/CT scan, and these seem to up-

stage 0% - 33% of the patients from LD seen on con-

ventional imaging to ED after PET scan [6,10,11]. These

results, however, have to be interpreted with caution

since the studies were small and half of them retro-

spective. However, the use of 18FDG-PET in the staging

of SCLC has increased in recent years. Azad A. et al. [11]

have evaluated the difference in overall survival in a re-

trospective group of 46 consecutive patients undergoing

staging by PET scans and found a significantly longer

overall survival in patients with LD on PET staging

compared with patients upstaged to ED on the PET scan

(median 18.6 months versus 5.9 months). However, this

result could easily be confounded by different subsequent

treatments.

One important question remains: Is the right staging in

patients with a low burden of metastatic disease clini-

cally important? These patients might benefit from a

combined treatment with CT and RT. In a randomized

study by Jeremic et al. [12], the effects of RT in patients

with SCLC-ED were evaluated. A total of 206 patients

with a complete response at distant sites and a complete

or partial response in the thorax after three cycles of CT

were randomized to either CT alone or accelerated hy-

perfractionated RT (54 Gy; 1.5 Gy/F). The median over-

all survival was found to be significantly higher in the

RT-group (17 months versus 11 months). Two other

trials are now ongoing to confirm this result (REST

(NTR 1527) and RTOG-0937) [13,14]. Until this matter

is properly clarified, it is of a great importance that pa-

tients are protected from potentially toxic thoracic RT as

a standard procedure.

During follow-up, only few isolated loco-regional re-

lapses (no = 5; 6%) and no isolated regional relapses

were observed. The RT was planned so only the primary

tumour and the pathological lymph nodes were encom-

passed with omission of ENI resulting in a smaller ra-

diation field. This strategy is, however, debated due to

the potential risk of increasing the isolated nodal failure

outside the radiation field. In 2006 two phase II [15,16]

studies was preformed to evaluate concurrent CT and

involved-field RT (45 Gy, 1.5 Gy/F) in 27 and 37 pa-

tients, respectively. Baas et al. [15] observed an isolated

regional relapse rate of 6% and De Ruysscher et al. [16]

a higher rate of 11%. In both studies the RT was based

solely on the pre-treatment CT imaging, and it was stated

that a more precise staging with an 18FDG-PET scan

might improve the rate of isolated regional nodal failures.

A prospective study [17], by the same Dutch research

group including De Ruysscher, in 2009 used 18FDG-PET

scans to make omission of ENI in 60 LD-SCLC patients

receiving concurrent CT (carboplatin and etoposide) to-

gether with twice-daily RT (45 Gy, 1.5 Gy/F) and

18FDG-PET/CT Is a Useful Tool in Staging Procedure before Chemo-Radiotherapy in Patients with

Limited Disease Small-Cell Lung Cancer. Pattern of Failure and Survival Is Analyzed 377

observed a low rate of isolated nodal failures (3%). How-

ever, it should be noticed that a difference in definition of

isolated nodal failure was used in this study compared to

the phase II trial by De Ruysscher et al. [16] making

comparison difficult. In 2010 18FDG-PET guided omi-

ssion of ENI was evaluated in a retrospective study by

Shirvani et al. [18], where data on 60 patients treated with

concurrent CT and RT resulting in a low rate of isolated

elective nodal failure (1.7%). In contrast to the pr eviou sly

mentioned study, intensity-modulated radiation therapy

(IMRT) was used and the authors concluded that omis-

sion of ENI was safe using a combination of 18FDG-PET

and IMRT. Recently, two studies [19,20] again evaluated

the omission of ENI guided by only a CT scan and found

low rates of loco-regional relapses in 108 and 38 patients

respectively, treated with RT concomitant with CT. In

our study, omission of ENI was guided by 18FDG-PET in

44% of the patients and by CT scan in the remaining, and

we observed no difference in locoregional relapse rate

between the two groups. Further studies are needed to

clarify the safety of omission of ENI. Results from two

ongoing studies [13] evaluating RT regimes are expected.

In the UK-led phase III CONVERT trial comparing the

twice-daily RT regime (45 Gy in 30F) with a once-daily

RT regime (66 Gy in 33 F), the use of ENI is not allowed.

This differs from the U S-led CALG B 30610 /RTOG 05 38

trial, evaluating three different RT regimes where medi-

astinal lymph nodes are irradiated electively.

Another question is timing of the RT. Several authors

support an early start of RT concomitant with CT [3,4,

21]. In a meta-analysis comparing phase III trials in

LD-SCLC, De Ruysscher [22] showed that the most

important predictor of five-year survival is the time from

the start of any treatment until the end of RT (SER). The

significantly higher five-year survival rate (>20%) was

found in patients with a short SER of less than 30 days.

In our study we had a median SER of 57 days with only

one patient having a SER shorter than 30 days.

We acknowledge that the limi tation of this stud y is the

small number of patients included and the retrospective

design. There were variations in the diagnostic work-up

and the treatment, resulting in the possibility of selection

bias for both the use of PET scans, imaging of the brain

and for the choice of treatment. PET/CT was incorpo-

rated in the diagnostic process during this time period

and there might be a selection bias due to the availability

of PET scanners. Patients were staged at three different

institutes and only one of the institutes had a specific

PET center. This could have influenced the patient

selection.

Carboplatin was the primary choice of platinum deri-

vative. This is in contrast to most other studies where

cisplatin is the treatment of choice and considered su-

perior to carboplatin. Whether this could have affected

the frequency of relapse and the overall survival is un-

known.

Despite the retrospective design of this study, the

population is consecutive and no patients were lost to

follow-up. Our data on relapse is therefore validated.

Time and course of death are validated as well due to a

complete registration of all patients in Denmark.

5. Conclusions

The pattern of failure in patients with LD-SCLC under-

going CT-RT showed that the challenge is still a very

high risk of distant metastases. The incidence of isolated

loco-regional failure was low, and this supports the

safety of a treatment strategy of selective irradiation of

pathological lymph nodes.

Patients staged with an 18FDG-PET/CT scan had a sig-

nificantly lower incidence of distant failure and a sig-

nificantly better overall survival compared to patients

staged with a CT scan only. This probably indicates the

value of including an 18PET-CT scan in the staging of

patients with SCLC before deciding on a treatment regi-

men.

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